Overarching Research Goals

Research in the Glembotski lab focuses on studies of cellular responses to physiological and pathological conditions, or stresses that challenge tissue viability and function. The overarching goals of the lab are to define signal transduction processes that are altered in cells in responses to stresses, such as a lack of oxygen and nutrients, known as ischemia, and how those processes remodel cells so they become more resilient to subsequent stresses. A better understanding of such protective stress responses is required in order to develop therapeutic approaches to treat chronic ailments, such as heart disease.

Specific Research Goals

Heart disease is the nation’s #1 cause of death, eclipsing the next five most frequent causes of death. Accordingly, the Glembotski lab focuses on basic science and translational heart disease research. Currently, our specific research goals are 1) to learn and understand the molecular mechanisms of heart disease, and 2) to convert what we learn to state-of-the-art therapies that could eventually reduce deaths due to heart disease.

The Glembotski lab is part of the Translational Cardiovascular Research Center (TCRC) in the Department of Internal Medicine at the The University of Arizona College of Medicine – Phoenix.

Mentorship and Training

The Glembotski lab provides a vibrant and rich training atmosphere for undergraduate and graduate students, as well as post-doctoral fellows in biomedical research. Training in the lab is based upon the premise that frequent communication with the Principal Investigator concerning project development and oversight will enhance productivity and trainee success. Trainees learn a method of scientific thinking, project development, time management, and manuscript and grant preparation that ensures success during the training, and well into the future. The goal is to prepare every trainee with the knowledge, scientific approach, credentials, published peer-reviewed papers and funded grants that are universally recognized indicators of success. Accordingly, the enterprising, hardworking, and thoughtful trainee will emerge from the lab armed with the ability to think and communicate effectively.

Career Opportunities

There are excellent research opportunities for scientists and trainees at all levels in the Glembotski lab.

Visiting Scientists and Post-doctoral Fellows interested in working in the lab are encouraged to contact Dr. Glembotski directly. Students interested in pursuing a MS or PhD, and interested in our research are encouraged to apply to the University of Arizona College of Medicine – Phoenix graduate programs in Clinical Translational Science.

News

Last updated on Oct 4, 2021 1 min read

Glembotski lab moved to University of Arizona College of Medicine in Phoenix

On September 1, 2020, Dr. Glembotski and his lab moved from SDSU to the University of Arizona College of Medicine in Phoenix, where he is serving as the inaugural Director of the Translational Cardiovascular Research Center and Professor of Medicine, the Associate Dean for Research and Professor of Medicine.

Research

ATF6 and Cardiac Growth

ER stress dysregulates ER proteostasis, which activates the transcription factor, ATF6, an inducer of genes that enhance protein folding and restore proteostasis. Due to increased protein synthesis, it is possible that protein folding and, thus, ER proteostasis are challenged during cardiac myocyte growth. However, it is not known whether ATF6 is activated, and if so, what its function is during hypertrophic growth of cardiac myocytes.

Pharmacologic Activation of ATF6

Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. In recent research done in the Glembotski lab, we used a mouse model of myocardial ischemia/reperfusion to show that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion with a new drug candidate we discovered in collaboration with scientists at The Scripps Research Institute, code named 147, transcriptionally reprogrammed proteostasis, ameliorated damage and preserved heart function in mice.

A Molecular Social Network- Cardiokine Secretion

One of the projects in the Glembotski lab involves identifying proteins secreted by the heart, determining what their functions are in myocardial function, as well as regenerating damaged heart tissue, and elucidating the mechanisms of their secretion.

ER Stress and the Unfolded Protein Response- Protein Quality Control in the Heart

Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to cardiovascular disease. In large part, the misfolding of proteins takes place during synthesis on free ribosomes in the cytoplasm, or on endoplasmic reticulum (ER) ribosomes.

Regenerative Medicine and Stem Cells

Proteins secreted by the heart are called cardiokines. After secretion, cardiokines, such as cytokines, growth promoters and stem cell homing factors, can reduce ischemic damage, as well as enhancing stem cell survival and engraftment. But ischemia impairs protein folding and secretion, and negatively impacts stem cell-mediated regeneration. However, we discovered a secretion process that resists this inhibition, enabling the release of certain beneficial cardiokines, just when they are needed the most. Studies in the Glembotski lab focus on examining the functions of, and molecular mechanisms governing this secretion process in cardiac myocytes and in cardiac stem cells. Our studies of cardiokine secretion in the ischemic heart, and secretion by cardiac stem cells will facilitate the design of therapeutic strategies aimed at enhancing the secretion of beneficial cardiokines that minimize damage and maximize regeneration.

Genomics and Gene Therapy

One of the main goals of research in the Glembotski lab is to develop prototypes of therapies that could be used as platforms for the development of novel treatments for heart disease. One such prototype involves the selective delivery of cardioprotective genes to the heart using an adenovirus-associated (AAV) gene therapy approach. In our studies of secretion, ER stress and stem cells in the heart, we have completed microarray analyses to identify mRNAs and microRNAs that are regulated in response to protective stress signaling pathways. As a result of those arrays, we have identified candidate genes that have been selected for development of prototypes for gene therapy. We have packaged the candidate genes into AAV9, a form of AAV that preferentially delivers genes to the heart. Moreover, we have engineered these genes so that their expression is regulated by cardiac-specific promoters, which further enhancing their utility and therapeutic safety. We have already shown the cardioprotective effects of several candidate genes using the AAV9 gene therapy approach, thus demonstrating the therapeutic potential of this platform for treating heart disease.

Proteomics and Protein Therapy

In efforts to develop novel therapies of treating heart disease, research in the Glembotski lab is focused on how to deliver cardioprotective agents to the heart without leaving a genetic footprint. One method to accomplish this is to deliver protective proteins directly to the heart using state-of-the-art protein formulation and transduction methods. One such method involves combining Tat- and Arg-9-mediated methods of protein transduction, with we identified as cardioprotective. To accomplish this, members of the lab have patented technologies for the generation of chimeric proteins so that the transduction domains are removed from the bioactive region of the proteins within cells of the heart. This approach has been used to develop a new therapeutic platform that can be applied in the future to the delivery of essentially any protective protein to any tissue of interest. Members of the Glembotski lab are encouraged to design novel therapeutic platforms, such as this, in order to optimize the application of our basic science research efforts to a therapeutic setting.

Christopher C. Glembotski

Professor of Medicine

Director, Translational
Cardiovascular Research Center

Associate Dean for Research

Department of Internal Medicine

Translational Cardiovascular Research Center (TCRC)

The University of Arizona College of Medicine – Phoenix

Principal Investigator

Dr. Glembotski is Professor of Medicine at the University of Arizona College of Medicine – Phoenix (UA COMP), where he is also Associate Dean for Research and Director of the Translational Cardiovascular Research Center. Dr. Glembotski earned a B.S. in biochemistry from California State Polytechnic University, San Luis Obispo, CA, and a Ph.D. in biochemistry from the University of California, Los Angeles. After a post-doctoral fellowship in cell and molecular physiology, in the Department of Physiology at the University of Colorado Health Sciences Center in Denver, Colorado, Dr. Glembotski joined the faculty in the Department of Pharmacology at the University of Pennsylvania School of Medicine in Philadelphia, PA., after which he moved to SDSU to become the Director of the SDSU Heart Institute, before moving to his current location at UA COMP.

Dr. Glembotski’s current research is in the area of molecular cardiology, with a focus on identifying signaling mechanisms in the heart that regulate the growth and survival of the myocardium during normal and pathological conditions. Recent studies in Dr. Glembotski’s lab have led to a better understanding of the heart’s natural defense mechanisms and to the design and implementation of therapeutic approaches to boost these defense mechanisms in order to make the heart more resistant to heart diseases, such as heart failure.

The Team

Principal Investigator

Christopher C. Glembotski

Professor of Medicine

Director, Translational
Cardiovascular Research Center

Associate Dean for Research

Lab Members

Alina S. Bilal

Research Professional

Atrial morphogenesis, development, and physiology, Chamber-specific gene regulation and miRNA expression, and their roles in pathophysiology, Inter-organ communication in systemic pathologies, Development of mouse models and AAV-based technology to advance cardiac research

Erik A. Blackwood

Faculty in Training

Non-canonical mediators of cellular proteostasis, Inter-organ communication in systemic pathologies, Small molecule and peptide-based therapeutic development, Small and large preclinical models of heart failure

Lauren MacDonnell

Research Professional

Utilizing molecular strategies to study the mechanisms and interactions involved in ER-associated degradation, Molecular cloning and construct design to create recombinant viral technology, Inter-organ communication in systemic pathologies

Sarah N. Parker

Research Professional

In vitro and in vivo evaluation of novel and combination chemotherapy treatments, Molecular mechanisms and risk factors of heart disease, Distribution of disease in human populations

Scott Hahn

Research Scientist

Sean Noudali

Research Professional

Pharmacology, Genetics, Animal physiology, Animal behavior

Victoria Murray

Research Professional

The multifactorial effects that heart disease and heart failure have on individuals afflicted with these conditions, Development of personalized medicine through the use of human iPSCs